When interacting with their environment animals constantly make decisions. These decisions frequently aim at maximizing reward while avoiding negative consequences such as energy costs, pain, or long-term disadvantages. Faced with a choice, animals consider and integrate several parameters such as their internal and behavioral state as well as external stimuli. Often decisions are shaped by prior experiences such as exposure to a given stimulus in a certain condition. But preferences and aversions can be innate, and an instinctive reaction can be essential to secure survival. Nevertheless, even these innate preferences need to be evaluated in a context-dependent manner and hence, context strongly impinges on behavior. While it is generally accepted that context influences behavior, our knowledge of the neural mechanisms of how internal state and external conditions alter ongoing behavior is scarce. The goal of my research is to provide a comprehensive understanding of the neural and molecular basis of context-specific behavior. To this end, my group studies how internal states shape chemosensory processing and behavior. In this talk, I will present two examples of our recent work in the fly on reproductive state-dependent decision making and on the role of need and motivation in foraging behavior.
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Mammals, including rodents show a broad range of defensive behaviors as a mean of coping with threatful stimuli including freezing and avoidance behaviors. Several studies emphasized the role of the dorsal medial prefrontal cortex (dmPFC) in encoding the acquisition as well as the expression of freezing behavior. However the role of this structure in processing avoidance behavior and the contribution of distinct prefrontal circuits to both freezing and avoidance responses are largely unknown. To further investigate the role of dmPFC circuits in encoding passive and active fear-coping strategies, we developed in the laboratory a novel behavioral paradigm in which a mouse has the possibility to choose either to passively freeze to an aversive stimulus or to actively avoid it as a function of contextual contingencies. Using this behavioral paradigm we investigated whether the same circuits mediate freezing and avoidance behaviors or if distinct neuronal circuits are involved. To address this question, we used a combination of behavioral, neuronal tracing, immunochemistry, single unit and patch clamp recordings and optogenetic approaches. Our results indicate that (i) dmPFC and dorsolateral and lateral periaqueductal grey (dl/lPAG) sub-regions are activated during avoidance behavior, (ii) a subpopulation of dmPFC neurons encode avoidance but not freezing behavior, (iii) this neuronal population project to the dl/lPAG, (iv) the optogenetic activation or inhibition of this pathway promoted and blocked the acquisition of conditioned avoidance and (v) avoidance learning was associated with the development of plasticity at dmPFC to dl/lPAG synapses. Together, these data demonstrate for the first time that activity-dependent plasticity in a subpopulation of dmPFC cells projecting to the dl/lPAG pathway controls avoidance learning.
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New behavioral and imaging findings with the cue-approach paradigm: A non-reinforced mechanism of behavior change

Sleep architecture carries important information about brain health. Here we show that active compared to quiet sleep in infants heralds a marked change from long- to short-range functional connectivity across broad-frequency neural activity. This change in cortical connectivity is attenuated following preterm birth and pre-empts visual performance at two years. Biophysical modeling shows that active sleep is defined by reduced energy in a large-scale, uniform mode of spatiotemporal neural activity and increased energy in two non-uniform anteroposterior modes. This distinct energy redistribution leads to the emergence of more complex connectivity patterns in active sleep compared to quiet sleep. Preterm-born infants show an attenuation in this sleep-related reorganization of connectivity that carries novel prognostic information.
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Late onset diseases such as cancer and neurodegenerative diseases represent an enormous burden in our ageing population. An in depth understanding of molecular pathomechanisms is a prerequisite for the development of novel treatment strategies. Our major research interest is in regulatory RNA-protein interactions, an important and often overlooked cellular phenomenon that plays an essential role in disease-development. RNA-function depends on the 3-dimensional structure of the RNA as well as on interaction with RNA-binding proteins. The main goal of our research is to identify and characterize regulatory RNA-protein interactions in healthy and disease tissue, especially in late onset diseases such as cancer and neurodegenerative diseases.In my group, we have identified an RNA-protein complex containing the ubiquitin ligase MID1 that plays an important role in regulating protein synthesis and that is significantly upregulated in late onset diseases including Huntington’s disease, Alzheimer’s disease or certain types of cancer. This aberrant MID1-activity leads to an increased protein production of proteins that are causal for disease-development.Thus, our data suggest that MID1 is a key regulator in disease development. Furthermore, our preliminary results indicate that MID1 localizes to cytosolic RNA granules and interacts with proteins involved in RNA granule assembly, RNA transport and local protein synthesis. In our ongoing experiments we further investigate the exact molecular function of MID1 and its interactome, especially focusing on the molecular pathways that are triggered by MID1 over-expression in disease tissue. Interestingly, these pathways include mTOR-signaling and insulin / insulin-like growth factor-1 (IGF-1) signaling pathways.
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Visceral organs have long been believed to act as major regulators of emotional state. However, the specific role of gut-borne signals in motivated behavior remains elusive to this day. The talk will describe the connectivity and behavioral functions of a neural circuit that links gut sensory neurons to brain reward systems. Implications for our current ideas on the role of the gut-brain axis will be discussed.
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Insights into Brain Metabolism by quantitative MRI: An Approach from Physics

On December 8, 2017, the 6th CGA Graduate Symposium will take place at the Max Planck Institute for Biology of Ageing. This festive Symposium takes place annually to celebrate the graduating students that have successfully completed their CGA curriculum. Twelve graduate students will present their work in different areas of ageing research. Each session will be accompanied by a key note lecture given by an invited, international renowned expert in ageing research. Our key note speakers will be Hayley Nicholls from Boston, U.S.A., David Tollervey from Edinburgh, UK and Marina Mapelli from Milan, Italy.Sponsored by Eppendorf, New England Biolabs, Eppendorf, Promega and Techniker Krankenkasse
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Brown adipose tissue (BAT) has the unique capacity to regulate energy expenditure by a process called adaptive thermogenesis, which dissipates chemical energy to produce heat. If fully active, the BAT depots of adult humans may burn an amount of energy equivalent to about 4 kg of white adipose tissue (WAT) per year. Needless to say, the identification of BAT in adult humans opens up completely new avenues of therapeutic intervention and offers unique scientific opportunities. This entails a need to better understand the molecular mechanisms that regulate BAT metabolism. This presentation is focused on how BAT, WAT and muscle regulate its uptake and use of substrates for metabolism and how this affects the function of these tissues. These studies have led to identification of transcription factors that regulate cellular glycolysis and substrate preference i.e. glucose or fatty acid uptake and further oxidation.
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Understanding the functional communication across brain has been a long sought-after goal of neuroscientists. However, due to the widespread and highly interconnected nature of brain circuits, the dynamic relationship between neuronal network elements remains elusive. With the development of optogenetic functional magnetic resonance imaging (ofMRI), it is now possible to observe whole-brain level network activity that results from modulating with millisecond-timescale resolution the activity of genetically, spatially, and topologically defined cell populations. ofMRI uniquely enables mapping global patterns of brain activity that result from the selective and precise control of neuronal populations. Advances in the molecular toolbox of optogenetics, as well as improvements in imaging technology, will bring ofMRI closer to its full potential. In particular, the integration of ultra-fast data acquisition, high SNR, and combinatorial optogenetics will enable powerful systems that can modulate and visualize brain activity in real-time. ofMRI is anticipated to play an important role in the dissection and control of network-level brain circuit function and dysfunction. In this talk, the ofMRI technology will be introduced with advanced approaches to bring it to its full potential, ending with examples of dissecting whole brain circuits associated with neurological diseases utilizing ofMRI.
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Type 2 diabetes (T2D) is a complex genetic metabolic disorder which has developed into major health problem responsible for early morbidities (e.g. severe vascular complications and cancers) and mortality, with a burden increasing globally. T2D results from the progressive alteration of insulin secretion from pancreatic beta cells on a background of impaired insulin action in sensitive organs and tissues. Whilst the environment is the key risk factor for T2D at the population level, one remarkable feature is the persistence of considerable individual disease risk amongst people sharing same environment. Estimates of T2D heritability range from 40 to 70%. Genome-wide association studies (GWAS) have identified >100 loci independently contributing to T2D risk. Despite this dramatic success, there has been a considerable gap between the knowledge of the genetic contribution of these loci and the understanding of how these loci physiologically impact the disease: indeed, association does not mean causality. Therefore, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to the poor knowledge of how these loci impact T2D pathophysiology. During my talk, I will present several post-GWAS functional studies which enabled the identification of causal genes and pathways involved in T2D pathophysiology.
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Regulation of Homeostatic Boundary Control and Rheostasis by the Melanocortin-3 Receptor

The hippocampus is a brain area that is involved in a variety of functions. In particular, the formation of memory and the codification of space depend on the functioning of the hippocampus. Virtually all areas of the hippocampus, and of most parts of the brain, contain excitatory and inhibitory neurons that form individual microcircuits. It is in the interaction between excitatory and inhibitory circuits where appropriate functional responses arise. We study how excitation and inhibition interact to activate neurons in the dentate gyrus of the hippocampus, one of the only regions of the brain in which new neurons are formed throughout life. In this seminar I will present experiments using electrophysiology and calcium imaging aiming to understand the functional role of newborn neurons in the processing of afferent stimuli, with the focus on the synaptic mechanism that generate the unique properties they present.
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Formaldehyde is a highly reactive chemical used as a preservative and also in many industrial processes. In our cells, this aldehyde is generated as a by-product of several essential biochemical pathways. This ‘endogenous’ formaldehyde is very reactive and can damage proteins and DNA resulting in lethal toxicity. Therefore, cells harbour two protective barriers: the formaldehyde-detoxifying enzyme alcohol dehydrogenase 5 (Adh5) and the Fanconi Anemia DNA repair pathway. The simultaneous inactivation of these two systems leads to haematopoietic stem cell attrition, kidney and liver dysfunction, and development of cancer in mice. My work aims to understand the molecular mechanisms that counteract unwanted consequences of essential metabolism.
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Role of Activin B as a novel hepatokine in the regulation of glucose homeostasis

The main interests of our work are the mechanisms underlying metabolic diseases, primarily obesity and insulin resistance. Mammals have two types of fat: brown and white, with opposing functions. Main role of the brown fat is to burn lipids and sugars to produce heat. Brown fat cells also emerge in the subcutaneous adipose tissue (named beige cells) in response to cold, a process known as browning. Promotion of increased brown fat development in humans and experimental mice leads to increased energy expenditure and lean and healthy phenotype without causing dysfunction in other tissues, suggesting the manipulation of the fat stores as an important therapeutic objective. The gut microbiota co-develops with the host and its composition is influenced by several physiological changes, which affect the whole-body metabolism and energy balance. With our integrative research program we are aiming to understand the mechanisms of white adipose tissue browning and the intestinal plasticity in regulating metabolic homeostasis and development of metabolic diseases from the gut microbiota related perspective.
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5th Graduate Symposium Cologne Graduate School of Ageing Research

Additionally, there will be talks from international guest speakers:
Malene Hansen on
"Cellular recycling: Role of autophagy in aging and disease",
David Rubinsztein on
"Autophagy and other pathways that protect against neurodegeneration",
Massimo Zeviani on
"New genes and mechanisms in mitochondrial biogenesis and disease"

Breast Cancer Swimming in a Sea of Lipid: On a voyage to discover the link between obesity and breast cancer

Helen and Robert Ellis Postdoctoral Senior Research Fellow, Head of Lipid Metabolism Laboratory, Charles Perkins Centre, School of Medical Sciences & Bosch Institute, Sydney Medical School, The University of Sydney

Brown adipose tissue (BAT) needs to dissipate vast amounts ofintracellular and circulating nutrients to sustain its exceptional oxidativemetabolic activity for thermogenesis, and in doing so BAT activity exertsbeneficial metabolic effects on obesity, insulin resistance andatherosclerosis. Identifying factors that protect adipocytes from metabolicstress during the adaptation to cold and obesity may hold great potentialtowards therapeutic approaches for metabolic diseases. As the dramaticmetabolic changes in BAT not only involve dissipation of energy-rich nutrientsbut also the de novo synthesis of new proteins, lipids and cellular organelles,adaptation to cold or excess nutrients might require special mechanisms forincreased quality control of these metabolic processes. While the endoplasmic reticulum (ER) is a critical organelle formetabolic homeostasis, the mechanisms that mediate adaptation of the ER inadipocytes are unclear. We will discuss novel insight into the molecularmechanisms guarding brown fat againstmetabolic stress in cold and obesity. In particular, we will focus on theunfolded protein response and ER-associated protein degradation as the mostcritical pathways by which the ER responds to increased metabolic demand anddiscuss how these are engaged in brown adipocytes. In this context, we haveidentified Nfe2l1, also known as Nrf1, as a novel regulator of ER homeostasisin BAT. Using in vitro systems and mouse models we will address thephysiological, pathological and translational relevance of Nfe2l1/Nrf1 for the adaptationof BAT to cold and obesity.
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The survival of an organism relies on its ability to promptly, effectively and reproducibly communicate with brain networks that control food intake and energy homeostasis. To achieve this, circulating factors of hunger and satiety reflecting nutrient availability must cross the blood-brain barrier (BBB) to reach effectors neurons. A defect in this process invariably leads to uncontrolled body weight. Here I will discuss the key role played in this process by a peculiar type of glial cells named tanycytes, which have their cell bodies lining the floor of the third ventricle and their endfeet contacting the pial surface of the brain. Recent studies indeed suggest that tanycytes, besides regulating hypothalamic BBB plasticity according to nutrient status, capture metabolic signals such as leptin from the bloodstream and transport them towards their cell body for release into the cerebrospinal fluid. Blockade of this conduit for peripheral metabolic factors into the brain of obese individuals is thought to contribute to the pathophysiology of central hormonal resistance.
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Editing of mouse and human genomes using CRISPR/Cas

Dr. Kühn is a tenured scientist at the Max-Delbrück-Center for Molecular Medicine & the Berlin Institute for Health, head of the Transgenic core facility and a lecturer for genetics at the Technical University of Munich in Germany. He has a long track record in mouse genetic engineering technology, including gene targeting in one-cell embryos using zinc-finger nucleases and TALEN. His current research is focused on utilizing and improving the efficiency of CRISPR/Cas9 based mutagenesis in mouse zygotes and human iPS cells, in particular the interference with non-homologous end joining to promote homology-directed repair.

Engineering of the mouse germline to create targeted mutants is a key technology for biomedical research. We use an expedite approach for the generation of mouse mutants by microinjection of engineered, sequence-specific nucleases into one-cell embryos. Such nucleases create targeted double-strand breaks (DSBs) and stimulate DNA repair by non-homologous end joining (NHEJ) or homology directed repair (HDR). NHEJ religates the open ends, frequently leading to frameshift (knockout) mutations by the loss of nucleotides, whereas HDR enables the insertion of targeted (knockin) mutations from gene targeting vectors or oligonucleotides as repair templates. By this means mutant knockout and knockin founders are identified 7 weeks after embryo injections, enabling the fast establishment of mutant lines. Three nuclease generations, ZFNs, TALENs and the CRISPR/Cas9 system were validated in recent years for direct mutagenesis in embryos. In particular, CRISPR/Cas9 enables the generation of knockout and knockin alleles at frequencies of up to 40% and 10%, respectively, among pups derived from embryo injections. Nevertheless, the dominance of NHEJ versus HDR requires further improvement. To tackle this problem we established `traffic light´ reporter lines indicating DSB repair by NHEJ or HDR through the expression of red or green fluorescent proteins. To enhance HDR, we suppressed NHEJ key molecules by gene silencing, by the inhibitor SCR7 or by the adenoviral proteins E1B55K and E4orf6. In cell lines, SCR7 or the knockdown of KU70 and DNA Ligase IV promotes the efficiency of HDR up to 5-fold. Coexpression of the DNA Ligase IV degrading E1B55K and E4orf6 proteins improves the efficiency of HDR up to 8-fold and essentially abolishes NHEJ repair. We are presently using TLR transgenic mice to enhance HDR repair of CRISPR/Cas-induced DSBs by NHEJ suppression in early embryos and somatic cells to optimize the generation of precisely targeted alleles in vivo.
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With the advent of modern sequencing techniques, regulatory RNA biology is gaining significant focus in myriads of avenues ranging from control of development to ageing and ageing-associated diseases. We bring together a group of young, internationally acclaimed scientists specializing in diverse aspects of RNA biology ranging from novel mechanisms of alternative splicing to single cell RNA sequencing. This will be a great opportunity to familiarize with the latest developments in regulatory RNA biology.
In order to facilitate easy and convenient scientific exchange, this symposium is free and registration is not required.
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